Development of the chemical exposure monitor with indoor positioning (CEMWIP) for workplace VOC surveys.

The purpose of this article was to research and develop a direct-reading exposure assessment method that combined a real-time location system with a wireless direct-reading personal chemical sensor. The personal chemical sensor was a photoionization device for detecting volatile organic compounds. The combined system was calibrated and tested against the same four standard gas concentrations and calibrated at one standard location and tested at four locations that included the standard locations. Data were wirelessly collected from the chemical sensor every 1.4 sec, for volatile organic compounds concentration, location, temperature, humidity, and time. Regression analysis of the photo-ionization device voltage response against calibration gases showed the chemical sensor had a limit of detection of 0.2 ppm. The real-time location system was accurate to 13 cm ± 6 cm (standard deviation) in an open area and to 57 cm ± 31 cm in a closed room where the radio frequency has to penetrate drywall-finished walls. The streaming data were collected and graphically displayed as a three-dimensional hazard map for assessment of peak exposure with location. A real-time personal exposure assessment device with indoor positioning was practical and provided new knowledge on direct reading exposure assessment methods.

Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 µg q4wk or Peg-IFNα-2a 180 µg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 µg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease.

Recent epidemiological studies have suggested an increased risk of venous thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of VTE in pulmonary fibrosis-associated mortality have not been published. Using data from the National Center for Health Statistics from 1988-2007, we determined the risk of VTE in decedents with pulmonary fibrosis in the USA. We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p<0.0001); males: 72.0 versus 74.4 yrs (p<0.0001)). Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data suggest a link between a pro-fibrotic and a pro-coagulant state.

The direct cellular target of topically applied pimecrolimus may not be infiltrating lymphocytes.

BACKGROUND: Topically applied calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis. When systemically administered, these agents cause immunosuppression via inhibition of calcineurin in lymphocytes. As topical agents, the mechanism of action is poorly defined. OBJECTIVES: To test the hypothesis that skin-infiltrating lymphocytes are directly targeted when calcineurin inhibitors are applied to the skin. METHODS: Ten patients with atopic dermatitis were treated with 1% pimecrolimus cream twice daily to target lesions. Skin biopsies were performed before and 48 h after beginning therapy. We assessed the cellular localization of NFAT1 and NFAT2 as a surrogate measure of intracellular calcineurin activity (e.g. increasing cytoplasmic localization with increasing calcineurin inhibition). RESULTS: All patients showed a clinical response, at both 48 h and 2 weeks. As previously described, NFAT2 localized to the follicular keratinocytes, and its activation was partially inhibited by topical pimecrolimus. NFAT1 was found to be expressed by follicular and interfollicular keratinocytes, and its mostly nuclear localization was not affected by topical pimecrolimus therapy. Both NFAT1 and NFAT2 were found in the infiltrating lymphocytes. However, using both manual counting as well as an automated method to assess nuclear intensity of NFAT staining, we found that the proportion of infiltrating leucocytes with nuclear ('activated') NFAT did not change following therapy with pimecrolimus. CONCLUSIONS: Our results suggest that topical pimecrolimus does not act primarily by inhibiting the calcineurin/NFAT axis in lymphocytes but may instead act by other mechanisms, possibly by decreasing NFAT2 activity in follicular keratinocytes.

Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1).

No therapy is known to improve health-related quality of life (HRQoL) or dyspnoea in patients with idiopathic pulmonary fibrosis. The present study investigated longitudinal changes in HRQoL and dyspnoea and explored the effects of bosentan on these end-points during the Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial. In total, 154 subjects received oral bosentan (n = 71) or placebo (n = 83). Changes in HRQoL and dyspnoea from baseline to month (M) 6 and up to M12 were measured using the St George's Respiratory Questionnaire (SGRQ), 36-item short-form health survey (SF-36), Transition Dyspnoea Index and Borg dyspnoea index. Overall, minimal changes occurred in measures of HRQoL and dyspnoea among placebo-treated subjects during the study. The effects of bosentan treatment on HRQoL and dyspnoea in the all-treated population were minimal. However, in the subset of subjects who had undergone surgical lung biopsy for diagnosis of idiopathic pulmonary fibrosis, treatment effects were observed up to M12 in the impact domain of the SGRQ and the physical functioning, general health and role emotional domains of the SF-36. HRQoL and dyspnoea changed minimally during the course of the present study. Observations from exploratory analyses suggested benefits of bosentan on HRQoL among patients who had undergone surgical lung biopsy for diagnosis, and they merit further investigation.

Exercise peripheral oxygen saturation (SpO2) accurately reflects arterial oxygen saturation (SaO2) and predicts mortality in systemic sclerosis.

BACKGROUND: Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (SpO2) and arterial oxygen saturation (SaO2) was examined and survival differences between subgroups of subjects stratified on SpO2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of SpO2. RESULTS: At maximal exercise the mean (SD) difference between SpO2 and SaO2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise SpO2 (Spo(2)max) fell below 89% or whose SpO2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose SpO2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose SpO2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). CONCLUSION: In patients with SSc-ILD, SpO2 is an adequate reflection of SaO2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, SpO2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.

Relationship between ionic perturbations and electrophysiologic changes in a canine Purkinje fiber model of ischemia and reperfusion.

Standard and ion-sensitive microelectrodes were used to identify the basis of electrophysiologic changes that occur in canine cardiac Purkinje fibers superfused with "ischemic" solution (40 min) and then returned to standard Tyrode's solution. Maximum diastolic potential (EMDP) decreased (-92.6 +/- 2.4 to -86.0 +/- 4.0 mV; n = 19; P less than 0.001) during exposure to "ischemia," and after reperfusion, rapidly hyperpolarized to -90.0 +/- 4.7 (2 min) and then depolarized to -47.0 +/- 7.5 mV (10 min; P less than 0.001). No significant change in intracellular K activity (alpha ik) was noted throughout. Extracellular K activity (alpha ek) changed only during reperfusion, reaching a nadir at 5 min (3.5 +/- 0.4 to 2.6 +/- 0.5 mM, P less than 0.03), and thus can not account for the decrease in EMDP during reperfusion. Mean alpha iNa increased (8.7 +/- 1.3 to 10.9 +/- 1.9 mM; n = 10; P less than 0.01) during ischemia, but rapidly declined during reperfusion to 5.1 +/- 2.2 mM (10 min; P less than 0.01). Exposure to acetylstrophanthidin (4-5 x 10(-7) M) during the final 10 min of ischemia increased alpha iNa to 19.9 +/- 3.8 mM (n = 5), which was unchanged at 5 min of reperfusion. This suggests that Na-K pump inhibition during ischemia was minimal and that the pump was stimulated early during reperfusion, accounting for the initial transient hyperpolarization. Resting tension did not change significantly during exposure to ischemia; however, return to control Tyrode's solution caused a marked rise to 11.3 +/- 9.9 mg/mm2 (n = 13, P less than 0.001). This is consistent with a calcium overload state during reperfusion. The depolarization seen during reperfusion may result from activation of a Ca-activated, nonselective cation channel or enhanced electrogenic Na/Ca exchange.

Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.

Monitoring of aromatic amine exposures in workers at a chemical plant with a known bladder cancer excess.

BACKGROUND: In April 1991, an excess of bladder cancer cases among workers employed at a chemical manufacturing facility in Niagara Falls, NY, was reported. This excess was primarily confined to 708 workers who had ever been employed in the rubber chemicals manufacturing area of the plant, where the aromatic amines aniline and o-toluidine have historically been used. PURPOSE: An environmental and biological monitoring survey was conducted to evaluate current exposures to aniline and o-toluidine in the rubber chemicals department. METHODS: Personal air sampling for aniline and o-toluidine was conducted with the use of a modified Occupational Safety and Health Administration (OSHA) 73 method. Urine samples were collected before and after work (i.e., pre-shift and post-shift, respectively) and stored at -70 degrees C. Base hydrolysis was used to convert acetanilide and N-acetyl-o-toluidine, metabolites of aniline and o-toluidine present in the urine, to the parent compounds. The parent compounds were extracted from the alkaline urine into butyl chloride and then back-extracted from the butyl chloride into aqueous hydrochloric acid. An aliquot of each acidic extract was subjected to ion-interaction reversed-phase liquid chromatography with coulometric electrochemical detection. Hemoglobin (Hb) was extracted from blood and stored at -70 degrees C. For the measurement of adducts of aniline, o-toluidine, and 4-aminobiphenyl (4-ABP), precipitated Hb was dissolved in 0.1 M sodium hydroxide in the presence of recovery standards, and the hydrolysate was extracted with hexane, derivatized with pentafluoropropionic anhydride, and analyzed by gas chromatography-mass spectrometry with negative chemical ionization. RESULTS: A total of 73 workers, including 46 of 64 exposed workers who were employed in the rubber chemicals department and had the potential for exposure to aniline and o-toluidine and 27 of 52 unexposed workers employed in other departments where aniline and o-toluidine were not used or produced, had data available for both aniline and o-toluidine and Hb adducts; 28 of the workers in the former group also had personal air-sampling data. Personal air sample measurements showed that airborne concentrations of aniline and o-toluidine were well within the limits allowed in the workplace by OSHA. Urinary aniline and o-toluidine levels, however, were substantially higher among exposed workers than among unexposed control subjects. The most striking differential was for post-shift urinary o-toluidine levels, which averaged (+/- standard deviation) 2.8 micrograms/L (+/- 1.4 micrograms/L) in unexposed subjects and 98.7 micrograms/L (+/- 119.4 micrograms/L) in exposed subjects (P = .0001). Average aniline-Hb and o-toluidine-Hb adduct levels were also significantly higher (P = .0001) among exposed workers than among unexposed control subjects. Average levels of adducts to 4-ABP, a potential contaminant of process chemicals, were not significantly different (P = .48), although three exposed workers had 4-ABP levels above the range in unexposed workers. CONCLUSIONS: The adduct data suggest that, among current workers, o-toluidine exposure substantially exceeds aniline exposure and that 4-ABP exposure, if it occurs at all, is not widespread. These data support the conclusion that occupational exposure to o-toluidine is the most likely causal agent of the bladder cancer excess observed among workers in the rubber chemicals department of the plant under study, although exposures to aniline and 4-ABP cannot be ruled out.

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.

Acute interstitial pneumonitis. Case series and review of the literature.

Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

Mitochondrial disease: a pulmonary and critical-care medicine perspective.

The clinical spectrum of mitochondrial diseases has expanded dramatically in the last decade. Abnormalities of mitochondrial function are now thought to participate in a number of common adult diseases, ranging from exercise intolerance to aging. This review outlines the common presentations of mitochondrial disease in ICUs and in the outpatient setting and discusses current diagnostic and therapeutic options as they pertain to the pulmonary and critical-care physician.

Interferon-gamma for delayed pulmonary toxicity syndrome resistant to steroids.

Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-gamma.

Procedure for the quantification of the biomarker (2-methoxyethoxy)acetic acid in human urine samples.

An accurate and precise procedure was developed for the detection and quantification of (2-methoxyethoxy)acetic acid (MEAA), a metabolite and biomarker for human exposure to 2-(2-methoxyethoxy)ethanol. The compound 2-(2-methoxyethoxy)ethanol has a wide array of industrial applications including its use as an additive in military jet fuel. Exposure to 2-(2-methoxyethoxy)ethanol is a health concern owing to its toxicity which includes developmental and teratogenic properties. Sample preparation consisted of liquid-liquid extraction (LLE) and esterification of MEAA to produce the ethyl ester. Measurement was by a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a HP-1 capillary column. Recovery studies of spiked blank urine demonstrated good accuracy and precision; recovery varied between 95 and 103% with relative standard deviations of 8.6% and less. The limit of detection (LOD) for this procedure was found to range from 0.02 to 0.08 microg/ml equivalent levels of MEAA in urine. These data and other aspects of the validation of this procedure will be discussed.

Toxic effects of hypoxia on neonatal cardiac function in the rat: alpha-adrenergic mechanisms.

Stimulation of peripheral alpha-adrenergic receptors by circulating catecholamines derived from the adrenal medulla is essential for surviving neonatal hypoxia. In 1-day-old rats, where sympathetic innervation of cardiovascular sites has not yet developed, blockade of these receptors results in failure of cardiac performance from a progressive decline in sinus rate and atrioventricular conduction deficits. These effects are absent in 8-day-old rats, where sympathetic efferent innervation has become established.

Autologous biologicals--science/regulations.

There has been increased interest in Targeted Biologicals in the United States for several reasons. First, new technology is available to facilitate science-based isolate selection and manufacture. The science of Autologous/Targeted Biologicals will be discussed later in this presentation. A second reason for the increased interest in Targeted Biologicals is the fact that the livestock production methods have changed to favour herd/flock specific products controlled by a veterinarian. There have been changes in management methods such as segregated early weaning in swine, accelerated feeding and early weaning of dairy calves, and forced moulting in poultry. Herds and flocks have increased in stocking density and size. These factors stress animals and may facilitate mutation, strain variation and increased virulence of pathogens. Under these conditions, Traditional Biologicals may not be relevant to current field isolates. Many veterinarians favour vaccinating only for pathogens isolated from a herd/flock. A third reason for the increased interest in these products is that the licensing procedure for Targeted Biologicals is responsive to the needs of livestock producers. The process is abbreviated, requiring much less time and money. This allows for a more rapid response to emerging pathogens, strain variations and mutations, while facilitating the development of monovalent and multivalent products for limited markets or those for minor species.

The therapist's management of intra-articular fractures.

Fabrication of the dynamic traction splint is described in step-by-step fashion in order to aid surgeons to understand the principles of application of the method and to assist hand therapists to make the splint. The new 6-inch diameter arcuate hoop and the radial or ulnar gutter base splint are detailed. Modification of continuous passive motion machines is described for use in conjunction with dynamic traction. Alternative splint applications and post-dynamic traction splinting therapy methods are outlined.